Studies have shown that resveratrol (trans-3,5,4'-trihydroxystilbene), a phytoalexin antioxidant found in grapes, red wines, berries and peanuts, imparts protection against several diseases. A plethora of pre-clinical studies have shown that resveratrol imparts chemopreventive as well as therapeutic response against several cancers. Further, resveratrol is being widely used as a supplement as well as a complementary and alternative medicine (CAM) approach for the management of several diseases/conditions. However, an important issue with resveratrol, especially in prevention settings (through diet or supplements), is believed to be its low bioavailability due to its rapid metabolism in mammals. It is known that during metabolism, the majority of resveratrol undergoes glucuronidation and sulfation. Studies have also shown that piperine, an alkaloid derived from black pepper (Piper spp.), inhibits glucuronidation in vivo. We believe that piperine will inhibit glucuronidation of resveratrol thereby enhancing its bioavailability leading to a superior chemopreventive response. This assumption is supported by our recent exciting preliminary data showing that piperine (20 mg/kg;oral gavage) enhances the bioavailability of resveratrol (500 mg/kg;oral gavage) in serum by ~175%. In this application, we propose to test the hypothesis that piperine will enhance the bioavailability of resveratrol leading to a superior chemopreventive and therapeutic response. In this application, we propose to conduct a clinical study (in human volunteers) as well as a preclinical trial (in a mouse model of prostate cancer. For our preclinical trial, we will conduct proof of principle study in a mouse model of prostate cancer (PCa). Our choice of PCa is based on the following point. PCa, next only to lung cancer, is the second leading cause of cancer related deaths in American males and because of its slow progression and long latency, is believed to be an ideal candidate disease for chemoprevention. Further, we have demonstrated that resveratrol imparts antiproliferative effects against human PCa cells, possibly via modulation of phosphatidylinositol 3'-kinase (PI3K)/Akt pathway and Bcl-2 family of proteins. Furthermore, recent studies have demonstrated that resveratrol suppresses PCa progression in TRAMP (transgenic adenocarcinoma of mouse prostate) and TRAP (Transgenic Rat for Adenocarcinoma of Prostate) models suggesting the potential of this agent for the prevention and treatment of PCa. The following two specific aims are proposed: 1) To determine the influence of piperine on the bioavailability of resveratrol in human volunteers;and 2) To determine if piperine coadministration enhances the bioavailability and chemopreventive effects of resveratrol on PCa development in TRAMP mice. We believe that a successful completion of this proposal may pave the way for the development of novel strategies to enhance the bioavailability of resveratrol. PUBLIC HEALTH RELEVANCE: Studies have shown that resveratrol, an antioxidant found in grapes, red wines, berries and peanuts, imparts protection against many diseases including certain cancers. Further, resveratrol is being widely used as a supplement as well as a complementary and alternative medicine (CAM) approach for the management of several diseases/conditions. However, an important issue with resveratrol, especially in prevention settings (through diet or supplements), is believed to be its low bioavailability due to its rapid metabolism in mammals. In this application, we will conduct a clinical study and a preclinical study to test the hypothesis that piperine (a chemical in black pepper) will enhance the bioavailability of resveratrol (via inhibiting its metabolism) leading to a superior chemopreventive and therapeutic response. We believe that a successful completion of this proposal may pave the way for the development of novel strategies to enhance the bioavailability and therefore preventive and/or therapeutic response of resveratrol.